The present invention relates to compounds which are antagonists of MCP-1 function and are useful in the prevention or treatment of chronic or acute inflammatory or autoimmune diseases, especially those associated with aberrant lymphocyte or monocyte accumulation such as arthritis, asthma, atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn""s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, and transplant rejection; and to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases.
Chemokines: Structure and Function
The migration of leukocytes from blood vessels into diseased tissues is an important process in the initiation of normal inflammatory responses to certain stimuli or insults to the immune system. However, this process is also involved in the onset and progression of life-threatening inflammatory and autoimmune diseases; blocking leukocyte recruitment in these disease states, therefore, can be an effective therapeutic strategy.
The mechanism by which leukocytes leave the bloodstream and accumulate at inflammatory sites involves three distinct steps: (1) rolling, (2) arrest and firm adhesion, and (3) transendothelial migration [Springer, Nature 346:425-433 (1990); Lawrence and Springer, Cell 65:859-873 (1991); Butcher, Cell 67:1033-1036 (1991)]. The second step is mediated at the molecular level by chemoattractant receptors on the surface of leukocytes which bind chemoattractant cytokines secreted by proinflammatory cells at the site of damage or infection. Receptor binding activates leukocytes, increases their adhesiveness to the endothelium, and promotes their transmigration into the affected tissue, where they can secrete inflammatory and chemoattractant cytokines and degradative proteases that act on the subendothelial matrix, facilitating the migration of additional leukocytes to the site of injury.
The chemoattractant cytokines, collectively known as xe2x80x9cchemokines,xe2x80x9d are a large family of low molecular weight (8 to 10 kD) proteins that share the ability to stimulate directed cell migration (xe2x80x9cchemotaxisxe2x80x9d) [Schall, Cytokine 3:165-183 (1991); Murphy, Rev Immun 12:593-633 (1994)].
Chemokines are characterized by the presence of four conserved cysteine residues and are grouped into two main subfamilies based on whether the two amino-terminal cysteines are separated by one amino acid (CXC subfamily, also known as xcex1-chemokines) or immediately adjacent to each other (CC subfamily, also referred to as xcex2-chemokines) [Baggiolini et al., Adv Immunol 55:97-179 (1994); Baggiolini et al., Annu Rev Immunol 15:675-705 (1997); Deng et al., Nature 381:661-666 (1996); Luster, New Engl J Med 338:436445 (1998); Saunders and Tarby, Drug Discovery Today 4:80-92 (1999)].
The chemokines of the CXC subfamily, represented by IL-8, are produced by a wide range of cells and act predominantly on neutrophils as mediators of acute inflammation. The CC chemokines, which include MCP-1, RANTES, MIP-1xcex1, and MIP-1xcex2, are also produced by a variety of cells, but these molecules act mainly on monocytes and lymphocytes in chronic inflammation.
Like many cytokines and growth factors, chemokines utilize both high and low affinity interactions to elicit full biological activity. Studies performed with labeled ligands have identified chemokine binding sites (xe2x80x9creceptorsxe2x80x9d) on the surface of neutrophils, monocytes, T cells, and eosinophils with affinities in the 500 pM to 10 nM range [Kelvin et al., J Leukoc Biol 54:604-612 (1993); Murphy, Annu Rev Immunol 12:593-633 (1994); Raport et al., J Leukoc Biol 59:18-23 (1996); Premack and Schall, Nature Med 2:1174-1178 (1996)]. The cloning of these receptors has revealed that cell surface high-affinity chemokine receptors belong to the seven transmembrane (xe2x80x9cserpentinexe2x80x9d) G-protein-coupled receptor (GPCR) superfamily.
Chemokine receptors are expressed on different cell types, including non-leukocyte cells. Some receptors are restricted to certain cells (e.g., the CXCR1 receptor is predominantly restricted to neutrophils), whereas others are more widely expressed (e.g., the CCR2 receptor is expressed on monocytes, T cells, natural killer cells, dendritic cells, and basophils).
Given that at least twice as many chemokines have been reported to date as there are receptors, there is a high degree of redundancy in the ligands and, not surprisingly, most chemokine receptors are rather promiscuous with regard to their binding partners. For example, both MIP-1xcex1 and RANTES bind to the CCR1 and CCR5 receptors, while IL-8 binds to the CXCR1 and CXCR2 receptors. Although most chemokines receptors bind more than one chemokine, CC receptors bind only CC chemokines, and CXC receptors bind only CXC chemokines. This ligand-receptor restriction may be related to the structural differences between CC and CXC chemokines, which have similar primary, secondary, and tertiary structures, but different quaternary structures [Lodi et al., Science 263:1762-1767 (1994)].
The binding of chemokines to their serpentine receptors is transduced into a variety of biochemical and physiological changes, including inhibition of cAMP synthesis, stimulation of cytosolic calcium influx, upregulation or activation of adhesion proteins, receptor desensitization and internalization, and cytoskeletal rearrangements leading to chemotaxis [Vaddi et al., J Immunol 153:4721-4732 (1994); Szabo et al., Eur J Immunol 27:1061-1068 (1997); Campbell et al., Science 279:381-384 (1998); Aragay et al., Proc Natl Acad Sci USA 95:2985-2990 (1998); Franci et al., J Immunol 157:5606-5612 (1996); Aramori et al., EMBO J 16:4606-4616 (1997);
Haribabu et al., J Biol Chem 272:28726-28731 (1997); Newton et al., Methods Enzymol 287:174-186 (1997)]. In the case of macrophages and neutrophils, chemokine binding also triggers cellular activation, resulting in lysozomal enzyme release and generation of toxic products from the respiratory burst [Newton et al., Methods Enzymol 287:174-186 (1997); Zachariae et al., J Exp Med 171:2177-2182 (1990); Vaddi et al., J Leukocyte Biol 55:756-762 (1994)]. The molecular details of the chemokine-receptor interactions responsible for inducing signal transduction, as well as the specific pathways that link binding to the above-mentioned physiological changes, are still being elucidated. Notwithstanding the complexity of these events, it has been shown that in the case of the MCP-1/CCR2 interaction, specific molecular features of MCP-1 can induce different conformations in CCR2 that are coupled to separate post-receptor pathways [Jarnagin et al., Biochemistry 38:16167-16177 (1999)]. Thus, it should be possible to identify ligands that inhibit chemotaxis without affecting other signaling events.
In addition to their high-affinity seven transmembrane GPCRs, chemokines of both subfamilies bind to various extracellular matrix proteins such as the glycosaminoglycans (GAGs) heparin, chondroitin sulfate, heparan sulfate, and dermatan sulfate with affinities in the middle nanomolar to millimolar range. These low-affinity chemokine-GAG interactions are believed to be critical not only for conformational activation of the ligands and presentation to their high-affinity serpentine receptors, but also for the induction of stable chemokine gradients that may function to stimulate haptotaxis (i.e., the migration of specific cell subtypes in response to a ligand gradient that is affixed upon the surface of endothelial cells or embedded within the extracellular matrix) [Witt and Lander, Curr Biol 4:394-400 (1994); Rot, Eur J Immunol 23:303-306 (1993); Webb et al., Proc Natl Acad Sci USA 90:7158-7162 (1993); Tanaka et al, Nature 361:79-82 (1993); Gilat et al., J Immunol 153:4899-4906 (1994)]. Similar ligand-GAG interactions have been described for a variety of cytokines and growth factors, including the various members of the FGF family, hepatocyte growth factor, IL-3 and IL-7, GM-CSF, and VEGF [Roberts et al., Nature 332:376-378 (1988); Gilat et al., Immunol Today 17:16-20 (1996); Clarke et al., Cytokine 7:325-330 (1995); Miao et al., J Biol Chem 271:4879-4886 (1996); Vlodavsky et al., Cancer Metastasis Rev 15:177-186 (1996)].
MCP-1 and Diseases
Chemokines have been implicated as important mediators of allergic, inflammatory and autoimmune disorders and diseases, such as asthma, atherosclerosis, glomerulonephritis, pancreatitis, restenosis, rheumatoid arthritis, diabetic nephropathy, pulmonary fibrosis, and transplant rejection. Accordingly, it has been postulated that the use of antagonists of chemokine function may help reverse or halt the progression of these disorders and diseases.
In particular, elevated expression of MCP-1 has been observed in a number of chronic inflammatory diseases [Proost et al., Int J Clin Lab Res 26:211-223 (1996); Taub, D. D. Cytokine Growth Factor Rev 7:355-376 (1996)] including rheumatoid arthritis [Robinson et al., Clin Exp Immunol 101:398-407 (1995); Hosaka et al., ibid. 97:451-457 (1994); Koch et al., J Clin Invest 90:772-779 (1992); Villiger et al., J Immunol 149:722-727 (1992)], asthma [Hsieh et al., J Allergy Clin Immunol 98:580-587 (1996); Alam et al., Am J Respir Crit Care Med 153:1398-1404 (1996); Kurashima et al., J Leukocyte Biol 59:313-316 (1996); Sugiyarna et al., Eur Respir J 8:1084-1090 (1995)], and atherosclerosis [Yla-Herttuala et al., Proc Natl Acad Sci USA 88:5252-5256 (1991); Nelken et al., J Clin Invest 88:1121-1127 (1991)].
MCP-1 appears to play a significant role during the early stages of allergic responses because of its ability to induce mast cell activation and LTC4 release into the airway, which directly induces AHR (airways hyper-responsiveness) [Campbell et al., J Immunol 163:2160-2167 (1999)].
MCP-1 has been found in the lungs of patients with idiopathic pulmonary fibrosis and is thought to be responsible for the influx of mononuclear phagocytes and the production of growth factors that stimulate mesenchymal cells and subsequent fibrosis [Antoniades et al., Proc Natl Acad Sci USA 89:5371-5375 (1992)]. In addition, MCP-1 is also involved in the accumulation of monocytes in pleural effusions, which is associated with both Mycobacterium tuberculosis infection and malignancy [Strieter et al., J Lab Clin Med 123:183-197 (1994)].
MCP-1 has also been shown to be constitutively expressed by synovial fibroblasts from rheumatoid arthritis patients, and its levels are higher in rheumatoid arthritis joints compared to normal joints or those from other arthritic diseases [Koch et al., J Clin Invest 90:772-779 (1992)]. These elevated levels of MCP-1 are probably responsible for the monocyte infiltration into the synovial tissue. Increased levels of synovial MIP-1xcex1 and RANTES have also been detected in patients with rheumatoid arthritis [Kundel et al., J Leukocyte Biol 59:6-12 (1996)].
MCP-1 also plays a critical role in the initiation and development of atherosclerotic lesions. MCP-1 is responsible for the recruitment of monocytes into atherosclerotic areas, as shown by immunohistochemistry of macrophage-rich arterial wall [Yla-Herttuala et al., Proc Natl Acad Sci USA 88:5252-5256 (1991); Nelken et al., J Clin Invest 88:1121-1127 (1991)] and anti-MCP-1 antibody detection [Takeya et al., Human Pathol 24:534-539 (1993)]. LDL-receptor/MCP-1-deficient and apoB-transgenic/MCP-1-deficient mice show significantly less lipid deposition and macrophage accumulation throughout their aortas compared with wild-type MCP-1 strains [Alcami et al., J Immunol 160:624-633 (1998); Gosling et al., J Clin Invest 103:773-778 (1999); Gu et al., Mol. Cell. 2:275-281 (1998); Boring et al., Nature 394:894-897 (1998).
Other inflammatory diseases marked by specific site elevations of MCP-1 include multiple sclerosis (MS), glomerulonephritis, and stroke.
These findings suggest that the discovery of compounds that block MCP-1 activity would be beneficial in treating inflammatory diseases.
Antagonists of Chemokine Function
Most chemokine antagonists reported to date are either neutralizing antibodies to specific chemokines or receptor-ligand antagonists, that is, agents that compete with specific chemokines for binding to their cognate serpentine receptors but, unlike the chemokines themselves, do not activate these receptors towards eliciting a functional response [Howard et al., Trend Biotechnol 14:46-51 (1996)].
The use of specific anti-chemokine antibodies has been shown to curtail inflammation in a number of animal models (e.g., anti-MIP-1xcex1 in bleomycin-induced pulmonary fibrosis [Smith et al., Leukocyte Biol 57:782-787 (1994)]; anti-IL-8 in reperfusion injury [Sekido et al., Nature 365:654-657 (1995)], and anti-MCP-1 in a rat model of glomerulonephritis [Wada et al., FASEB J 10:1418-1425 (1996)]). In the MRL-lpr mouse arthritis model, administration of an MCP-1 antagonist significantly reduced the overall histopathological score after the early onset of the disease [Gong et al., J Exp Med 186:131-137 (1997)].
A major problem associated with using antibodies to antagonize chemokine function is that they must be humanized before use in chronic human diseases. Furthermore, the ability of multiple chemokines to bind and activate a single receptor forces the development of a multiple antibody strategy or the use of cross-reactive antibodies in order to completely block or prevent pathological conditions.
Several small molecule antagonists of chemokine receptor function have been reported in the scientific and patent literature [White, J Biol Chem 273:10095-10098 (1998); Hesselgesser, J Biol Chem 273:15687-15692 (1998); Bright et al., BioorgMed Chem Lett 8:771-774 (1998); Lapierre, 26th Natl Med Chem Symposium, June 14-18, Richmond (Va.), USA (1998); Forbes et al., Bioorg Med Chem Lett 10:1803-18064 (2000); Kato et al., WO 97/24325; Shiota et al., WO 97/44329; Naya et al., WO 98/04554; Takeda Industries, JP 09-55572 (1998); Schwender et al., WO 98/02151; Hagmann et al., WO 98/27815; Connor et al., WO 98/06703; Wellington et al., U.S. Pat. No. 6,288,103].
The specificity of the chemokine receptor antagonists, however, suggests that inflammatory disorders characterized by multiple or redundant chemokine expression profiles will be relatively more refractory to treatment by these agents.
A different approach to target chemokine function would involve the use of compounds that disrupt the chemokine-GAG interaction. One class of such agents with potential therapeutic application would consist of small organic molecules that bind to the chemokine low affinity GAG-binding domain.
Compounds of this class might not inhibit binding of the chemokine to its high-affinity receptor per se, but would disrupt chemokine localization within the extracellular matrix and provide an effective block for directed leukocyte-taxis within tissues. An advantage of this strategy is the fact that most CC and CXC chemokines possess similar C-terminal protein folding domains that define the GAG-binding site, and, hence, such compounds would be more useful for the treatment of inflammatory disorders induced by multiple, functionally redundant chemokines [McFadden and Kelvin, Biochem Pharmacol 54:1271-1280 (1997)].
The use of small molecule drugs to bind cytokine ligands and disrupt interactions with extracellular GAGs has been reported with FGF-dependent angiogenesis [Folkman and Shing, Adv Exp Med Biol 313:355-364 (1992)]. For example, the heparinoids suramin and pentosan polysulphate both inhibit angiogenesis under conditions where heparin is either ineffective or even stimulatory [Wellstein and Czubayko, Breast Cancer Res Treat 38:109-119 (1996)]. In the case of suramin, the anti-angiogenic capacity of the drug has also been shown to be targeted against VEGF [Waltenberger et al., J Mol Cell Cardiol 28:1523-1529 (1996)] which, like FGF, possesses heparin-binding domains similar to those of the chemokines. Heparin or heparin sulphate has also been shown to directly compete for GAG interactions critical for T-cell adhesion mediated by MIP-1xcex2 in vitro [Tanaka et al., Nature 361:79-82 (1993)].
The disclosures of all documents referred to throughout this application are incorporated herein by reference.
The present invention relates to compounds that inhibit MCP-1-induced chemotaxis of human monocytic cells both in vitro and in vivo. These novel MCP-1 antagonists are useful for the treatment of inflammatory diseases, especially those associated with lymphocyte and/or monocyte accumulation, such as atherosclerosis, diabetic nephropathy, inflammatory bowel disease, Crohn""s disease, multiple sclerosis, nephritis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, and other chronic or acute autoimmune disorders. In addition, these compounds can be used in the treatment of allergic hypersensitivity disorders, such as asthma and allergic rhinitis, characterized by basophil activation and eosinophil recruitment.
A first embodiment of the present invention provides compounds of Formula I, Formula II, and Formula III: 
where:
n is an integer of 0 to 4 in Formula I, and is an integer of 0 to 2 in Formula, II and Formula III:
X and Y are independently O, S, CHxe2x80x94R8, or Nxe2x80x94R7 in Formula I and Formula II, and are independently N and Cxe2x80x94R8 in Formula III;
Z is N or Cxe2x80x94R8;
provided that at least one of X, Y, and Z is a non-carbon ring atom;
each R1 is independently, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94CF3, halogen, nitro, xe2x80x94CN, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94NR9R10, xe2x80x94NR9(CH2)1-6C (xe2x95x90O)OR10, xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90O)R9, xe2x80x94SO2R9, xe2x80x94OSO2R9, xe2x80x94SO2NR9R10, xe2x80x94NR9SO2R10 or xe2x80x94NR9C(xe2x95x90O)R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group, or in Fornula I, n=2 and the two R1""s together constitute xe2x95x90O,
R2, R3, and R8 are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94CF3, halogen, nitro, xe2x80x94CN, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94NR9R10, xe2x80x94NR9(CH2)1-6C(xe2x95x90O)OR10, xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90O)R9, xe2x80x94SO2R9, xe2x80x94OSO2R9, xe2x80x94SO2NR9R10, xe2x80x94NR9SO2R10 or xe2x80x94NR9C(xe2x95x90O)R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group,
Each R7 is independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, substituted aryl, aryl(lower alkyl), substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9, C(xe2x95x90O)NR9R10, xe2x80x94SO2OR9, xe2x80x94SO2NR9R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group,
R4 and R5 are independently, hydrogen, optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted aryl(lower alkyl), or, together, are xe2x80x94(CH2)2-4xe2x80x94,
R6 is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted aryl(lower alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl), xe2x80x94C(xe2x95x90O)R11, xe2x80x94C(xe2x95x90O)OR11, xe2x80x94C(xe2x95x90O)NR11R12, xe2x80x94SO2R11, or xe2x80x94SO2NR11R12, wherein R11 and R12 are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R11 and R12 together are xe2x80x94(CH2)4-6xe2x80x94,
or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.
The compounds of this invention may possess one or more chiral centers, and can therefore exist as individual stereoisomers or as mixtures of stereoisomers. In addition, some of the compounds of Formula I, Formula II, and Formula III are capable of further forming pharmaceutically acceptable salts and esters. The compounds of this invention may further exist in tautomeric forms and can therefore be produced as individual tautomeric forms or as mixtures of tautomeric forms. Unless indicated otherwise, the description or naming of a compound or groups of compounds is intended to include both the individual isomers or mixtures (racemic or otherwise) of stereoisomers and their tautomeric forms. Methods for the determination of stereochemistry and the separation of stereoisomers are well known to a person of ordinary skill in the art [see the discussion in Chapter 4 of March J.: Advanced Organic Chemistry, 4th ed. John Wiley and Sons, New York, NY., 1992]. All of these stereoisomers and pharmaceutical forms are intended to be included within the scope of the present invention.
A second embodiment of the present invention provides compounds of Formula Ia, Formula IIa, or Formula IIIa: 
where:
m is an integer of 0 to 4;
n is an integer of 0 to 4 in Formula Ia, and is an integer of 0 to 2 in Formula IIa and Formula IIIa;
X and Y are independently O, S, CHxe2x80x94R8, or Nxe2x80x94R7 in Formula Ia and Formula IIa, and are independently N and Cxe2x80x94R8 in Formula IIIa;
Z is N or Cxe2x80x94R8;
provided that at least one of X, Y, and Z is a non-carbon ring atom; each R1 is independently, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94CF3, halogen, nitro, xe2x80x94CN, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94NR9R10, xe2x80x94NR9(CH2)1-6C(xe2x95x90O)OR10, xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9, xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94OC(xe2x95x90O)R9, xe2x80x94SO2R9, xe2x80x94OSO2R9,xe2x80x94SO2NR9R10, xe2x80x94NR9SO2R10 or xe2x80x94NR9C(xe2x95x90O)R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group, or in Formula I, n=2 and the two R1""s together constitute xe2x95x90O,
R2, R3 and R8 are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94CF3, halogen, nitro, xe2x80x94CN, xe2x80x94OR9, xe2x80x94SR9, xe2x80x94NR9R10, xe2x80x94NR9R10, xe2x80x94NR9(CH2)1-6C(xe2x95x90O)OR10, xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9, xe2x80x94C(xe2x95x90O)NR9R10,xe2x80x94OC(xe2x95x90O)R9, xe2x80x94SO2R9, xe2x80x94OSO2R9, xe2x80x94SO2NR9R10, xe2x80x94NR9SO2R10 or xe2x80x94NR9C(xe2x95x90O)R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group,
each R7 is independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), aryl, substituted aryl, aryl(lower alkyl), substituted aryl(lower alkyl), halo(lower alkyl), xe2x80x94C(xe2x95x90O)R9, xe2x80x94C(xe2x95x90O)OR9; xe2x80x94C(xe2x95x90O)NR9R10, xe2x80x94SO2OR9, xe2x80x94SO2NR9R10, wherein R9 and R10 are independently, hydrogen, optionally substituted lower alkyl, lower alkyl-N(C1-2 alkyl)2, lower alkyl(optionally substituted heterocycloalkyl), alkenyl, alkynyl, optionally substituted cycloalkyl, cycloalkyl(lower alkyl), optionally substituted heterocycloalkyl(lower alkyl), aryl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl), or R9 and R10 together are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH, N-(aryl), N-(aryl(lower alkyl)), Nxe2x80x94(CH2)1-6C(xe2x95x90O)OR (where R is hydrogen or lower alkyl) or N-(optionally substituted C1-2 alkyl) group,
R4 and R5 are independently, hydrogen, lower alkyl optionally substituted lower alkyl, optionally substituted aryl, or optionally substituted aryl(lower alkyl), or, together, are xe2x80x94(CH2)2-4xe2x80x94,
R13 is hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl(lower alkyl), heterocycloalkyl, optionally substituted aryl, optionally substituted aryl(lower alkyl), optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl), halo(lower alkyl), xe2x80x94CF3, halogen, nitro, xe2x80x94CN, xe2x80x94OR15, xe2x80x94SR15, xe2x80x94NR15R 16, xe2x80x94C(xe2x95x90O)R15, xe2x80x94C(xe2x95x90O)OR15, xe2x80x94C(xe2x95x90O)NR15R16, xe2x80x94OC(xe2x95x90O)R15, xe2x80x94SO2R15, xe2x80x94SO2NR15R16, xe2x80x94NR15SO2R16 or xe2x80x94NR15C(xe2x95x90O)R16, wherein R15 and R16 are independently, hydrogen, optionally substituted lower alkyl, alkenyl, alkynyl, xe2x80x94CF3, cycloalkyl, optionally substituted heterocycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroaryl(lower alkyl) or, together, are xe2x80x94(CH2)4-6xe2x80x94 optionally interrupted by one O, S, NH or Nxe2x80x94(C1-2 alkyl) group, and
each R14 is independently selected from optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, halogen, xe2x80x94CF3, xe2x80x94OR17 xe2x80x94NR17R18, xe2x80x94C(xe2x95x90O)R17, xe2x80x94C(xe2x95x90O)OR17, xe2x80x94C(xe2x95x90O)NR17R18, wherein R17 and R18 are independently, hydrogen, lower alkyl, alkenyl, alkynyl, xe2x80x94CF3, optionally substituted heterocycloalkyl, cycloalkyl, cycloalkyl(lower alkyl), optionally substituted aryl, heteroaryl, heteroaryl(lower alkyl) or, together, are xe2x80x94(CH2)4-6xe2x80x94, optionally interrupted by one O, S, NH or Nxe2x80x94(C1-2 alkyl) group,
or a pharmaceutically acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.
Preferred compounds of the second embodiment are:
1. compounds of Formula Ia, where X and Y are O, Z is Cxe2x80x94H, and n=0.
2. compounds of Formula Ia, where X and Y are O, Z is Cxe2x80x94H, and each R1 is lower alkyl.
3. compounds of Formula Ia, where X is O, Y is Nxe2x80x94R7, where R7 is hydrogen or lower alkyl, Z is Cxe2x80x94H, and each R is lower alkyl.
4. compounds of Formula Ia, where X is Nxe2x80x94R7, where R7 is hydrogen or lower alkyl, Y is O, Z is Cxe2x80x94H, and each R is lower alkyl.
5. compounds of Formula Ia, where X and Y are each Nxe2x80x94R7, where R7 is hydrogen, lower alkyl, substituted lower alkyl, or optionally substituted aryl(lower alkyl), Z is Cxe2x80x94H, and each R1 is lower alkyl.
6. compounds of Formula IIIa, where X and Y are N, Z is Cxe2x80x94H, and n=0.
7. compounds of Formula IIIa, where X and Y are N, Z is Cxe2x80x94H, and each R1 is lower alkyl.
8. compounds of the second embodiment where R2 and R3 are independently selected from hydrogen, lower alkyl or halogen.
9. compounds of the second embodiment where R4 and R5 are independently selected from hydrogen or lower alkyl.
10. compounds of the second embodiment, where R13 is independently selected from aryl, substituted aryl, -heteroaryl or optionally substituted heteroaryl, halogen, xe2x80x94CF3, xe2x80x94CN, xe2x80x94OR15, or xe2x80x94CO2R15, wherein R15 is hydrogen, lower alkyl or optionally substituted aryl.
11. compounds of the second embodiment, where each R14 is independently selected from halogen, xe2x80x94CF3, xe2x80x94OR, xe2x80x94CO2R17, or xe2x80x94OCH2CO2R17, wherein R17 is hydrogen, lower alkyl or optionally substituted aryl.
A third embodiment of the present invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of this invention.
A fourth embodiment of the present invention provides methods for treating a disease treatable by the administration of an MCP-1 inhibitor, for example, chronic or acute inflammatory or autoimmune diseases such as asthma, atherosclerosis, diabetic nephropathy, glomerulonephritis, inflammatory bowel disease, Crohn""s disease, multiple sclerosis, pancreatitis, pulmonary fibrosis, psoriasis, restenosis, rheumatoid arthritis, or transplant rejection, in a mammal in need thereof, comprising the administration to such mammal of a therapeutically effective amount of at least one compound of this invention or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same.
A fifth embodiment of this invention provides a process for the preparation of the compounds of the invention or pharmaceutically acceptable salts thereof.